The skeleton provides a rigid, protective frame for the rest of the body and large injuries or defects can be incapacitating. In particular, the treatment f segmental defects remains an unresolved problem today. Autogenous bone graft is limited in supply and the biological activity of bone graft substitutes requires further refinement. Thus, new strategies for more physiological healing of critical sized bone defects are much needed. Studying models for bone regeneration in small mammals is a vital first step to developing treatments for severe skeletal injuries. Although humans do not repair as well as amphibians, human adults demonstrate a remarkable ability to regenerate large portions of the rib (>6 inches). We have developed a mouse model for rib repair that is amenable to genetic and surgical manipulation. Our preliminary studies have shown that 1) complete repair occurs within 1-2 months, 2) regrowth occurs in the middle of the resection site as well as from the ends, and 3), that the presence of the surrounding connective tissue sheath, or periosteum, is required for complete healing to occur. Based on our preliminary findings we now aim 1) to determine what steps occur to build new bone with the expectation that a rapidly produced cartilage intermediate is key and 2) to determine if the cells involved in the repair arise from progenitors in the periosteum. Our ultimate goal is to harness the unique features of rib skeletal repair to develop methods for enhancing bone healing in other locations of the body.